The primary aim of this project is to increase our understanding of the role of the serotonergic neurotransmitter system in behavior. Animal model studies described in this project are done in parallel with analogous studies of genes affecting serotonergic neurotransmission in healthy humans and in patients with obsessive-compulsive disorder and other anxiety disorders as described in our other project report. In the last year, we have extended the characterization of mice with a targeted disruption of the serotonin (5-HT) transporter. These mice, which have a 50% reduction (in +/- mice) and a complete lack (in -/- mice) of the transporter, demonstrate a spontaneous behavioral phenotype of increased "anxiety in several models of rodent conflict behavior as well as greater neuroendocrine responses to stressful conditions. Responses to two drugs of abuse, MDMA (3,4-methylenedioxymeth-amphetamine, "ecstasy") and cocaine, and to several other drugs were found to be gene-dose-dependently altered in these "knock-out" mice. Other drug responses were only altered in -/- mice; some of these reflected expected desensitization of 5-HT-1A, and other serotonin receptor subtypes as well as changes in post-receptor signaling mechanisms.